The proposed research is directed toward understanding the molecular and biochemical basis of the actions of histamine on the mammalian heart. Toward this end we will examine the effects of histamine, histamine analogs, and histamine antagonists on cardiac adenyl cyclase in broken cell preparations from different species, different regions of the heart, and different subcellular fractions. The specificity of the effects of histamine on the cardiac enzyme will be examined by the use of specific antagonists for histamine and other cardiac receptors. The results of these biochemical studies will be correlated with the inotropic and chronotropic effects of histamine and its antagonists on intact atrial or ventricular muscle preparations. We will conduct a kinetic analysis of the histamine-sensitive cardiac adenyl cyclase by computer fitting and simulation techniques in order to study possible mechanisms for the effects of histamine, divalent cations, and guanyl nucleotides on the enzyme and to aid in the design of future experiments. Structure-activity studies will be carried out on the histamine-stimulated adenyl cyclase and on cardiac contractility and the techniques of theoretical chemistry will be used to rationalize these data and to explore possible mechanisms of receptor activation by histamine and related compounds. Direct studies of histamine-receptor interactions will be carried out by means of binding studies using labeled compounds and these results will be correlated with the studies on adenyl cyclase and on intact muscle preparations.